Abstract The mechanical microenvironments have profound effects on the morphology and mechanical properties of cells, which are required for their functions. Pluripotent stem cells (PSCs) grow as a multicellular colony and the coupling effects of cell-cell and cell-ECM interactions are complex, while they are necessary for formations and functions of tissues. We used the finite element method to develop a computational model of a pair of deformed PSCs in contact with each other in three dimensions, and the growth and depolymerization of actin filaments were considered. We demonstrated the effects of substrate stiffness on the morphology of cells and nuclei and the rearrangement of cytoskeleton. The results show that as the substrate becomes softer, the nuclei become loose and round, and the actin filaments are assembled at a lower level. These changes could promote the formation of compacted cell colony which have a positive effect on the maintenance of pluripotency and the efficiency of induced reprogramming. We also find that stronger activation of cytoskeleton contractility will compress the cytoplasm as well as the nuclei. The cell mechanical model proposed here provides a strategy to study the response of cell morphology and cytoskeleton of the two-cell system under different biophysical stimuli. Since the nuclear morphology affects the remodeling of chromatin and the transcription efficiency of pluripotent genes, it provides a fundament for a further study of more mechanical factors on cell pluripotency.